The overall goal of this proposal is to develop and commercialize a novel biologic therapy for the treatment of allergic disease and particularly allergic asthma. Specifically, this proposal will provide the critical immunogenicity, mechanistic and biomarker data that will position a novel biologic, GE2, for human clinical trials in allergic disease. The therapeutic molecule is a genetically engineered human fusion protein consisting of a portion of the human gamma1 Fc linked to a portion of the human epsilon Fc chain [(hinge-h2-3(1)-linker- (ch2-3-4()] that is designated as "GE2". Effective treatments for severe inhalant allergy/asthma and food allergy represent major unmet needs. Asthma affects 5-10% of the US population or an estimated 14-15 million persons, including 5 million children. There were an estimated 1.8 million US emergency department visits, 500,000 hospitalizations and 5000 deaths annually and an increase of over 100% in the United States between 1985 and 1997 with these trends stabilizing more recently. This proposal is designed to address safety and biomarker experiments that are critical for the successful development GE2. Extensive preclinical mechanistic and therapeutic studies have both defined the optimal molecule design and shown its therapeutic efficacy. We are now poised to move GE2 studies to human clinical trials. However, the key remaining question is the potential in vivo immunogenicity of the GE2 molecule. This question assumes particular importance given the targeting of GE2 to the high affinity IgE receptor (FcRI) on mast cells and basophils whereby immunogenicity might not only inhibit GE2's function but could lead to serious adverse effects. Thus, Phase I of the grant proposal is designed to test the hypothesis that GE2 is not immunogenic in homologous animals using rhesus monkeys, provide key mechanistic information and biomarkers and lay the groundwork to make the human GE2 for IND-enabling and phase 1 human studies. Phase II of this proposal is designed to complete the key experimental pre-clinical steps on the path to commercialization. To achieve this goal, we will produce rhesus GE2 (rhGE2) for immunogenicity and mechanistic studies and derive a stable high-expressing human GE2 (hGE2) CHO cell line for Phase II of the proposed grant. Rhesus macaques will be given rhGE2 subcutaneously at four-week intervals (control, 1 mg/kg, 10 mg/kg) for a total of 3 doses. GE2's immunogenicity will be assessed by testing animals for the development of anti-GE2 antibodies over the 3- month protocol. Simultaneously, we will test whether GE2 (1) inhibits IgE production and (2) decreases circulating basophils in non-human primates, two important mechanistic endpoints and potential biomarkers for future phase 1 clinical trials will be assessed. Once completed, this proposal will provide the critical immunogenicity, mechanistic and biomarker data that will position this novel biologic for human clinical trials in allergic disease. PUBLIC HEALTH RELEVANCE: Effective treatments to for severe allergic asthma and food allergy represent a major unmet medical need. Asthma affects 5-10% of the US population, an estimated 14-15 million persons, including 5 million children resulting in lost work and school time of approximately 100 million days with more than 1.8 million annual US emergency department visits. The goal of this proposal is to develop and commercialize a novel human biologic capable of inhibiting acute allergic reactions as a treatment for severe allergy disease.